Search Results for: Biomarcatori nella saliva per la diagnosi precoce dell’Alzheimer

Stroke, Volume 55, Issue Suppl_1, Page ATP23-ATP23, February 1, 2024. Introduction:The vascular contribution to Alzheimer’s disease (AD) and AD-related dementias is increasingly recognized. Scanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina, vascular changes and amyloid plaque deposition. The relationship between retinal vascular changes and peri-vascular amyloid deposition in the continuum of neurodegeneration is imperfectly understood. In this exploratory topographic analysis of a cohort of subjects with normal and impaired cognition that underwent SLO, we investigated the retinal vascular-adjacent (para-vascular) amyloid plaque distribution and its correlation with cognitive measures.Methods:34 subjects with cognitive decline underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal para-arteriolar and para-venular curcumin positive amyloid plaques were quantified in the supero-temporal retinal quadrant, in the first-, second- and third-order retinal vascular branches. The para-venous and para-arteriolar amyloid count were compared between patients with normal and impaired cognition, and their correlation with brain volumes and white matter hyperintensities was determined.Results:We analyzed retinal para-venous and para-arteriolar amyloid and vascular-structural parameters derived from 29 subjects, mean (SD) age 65(7), 48% female. Para-arteriolar plaque was higher than para-venular plaque in the entire cohort (p

Stroke, Volume 55, Issue Suppl_1, Page ATP162-ATP162, February 1, 2024. Introduction:Intracerebral hemorrhage (ICH) has high morbidity and mortality without available targets for intervention. Polyamines are metabolites implicated in neurological diseases such as traumatic brain injury, Alzheimer’s Disease, and ischemic stroke. No studies have evaluated polyamines as they relate to ICH occurrence or outcomes. In this pilot study, we sought preliminary data on whether polyamines could be potential novel targets to improve outcomes after ICH.Methods:We analyzed plasma samples from 7 ICH cases and 10 control participants from the Genetics and Environmental Risk Factors for Stroke (GERFHS) IV study for polyamine measurements using Capillary Electrophoresis with Laser Induced Fluorescence Detection with the modality of Micellar Electrokinetic Chromatography. Plasma samples were deproteinized and derivatized with Fluorescein Isothiocyanate. Samples were spiked with standard solutions and compared with standard curves developed per each polyamine. We report median age and sex of the cohort. Peak spermine, spermidine and putrescine levels were compared using a student’s t-test.Results:In this pilot study of participants enrolled into GERFHS IV (median age 67 vs 61, cases vs controls respectively, 50% female) all three unacetylated polyamine levels were higher in cases. Although sample size is modest, there was a trend towards increased spermidine levels with higher mRS at 90 days (r2= 0.3342) (Figure 1).Conclusions:For the first time, we have shown that polyamines are elevated after ICH, and that higher polyamine levels may be associated with worse outcomes. This preliminary data supports further evaluation of polyamines as potential targets to improve outcomes after ICH in a larger cohort.

Stroke, Volume 55, Issue Suppl_1, Page AWMP14-AWMP14, February 1, 2024. Background:Cerebral amyloid angiopathy (CAA) is associated with reduced cerebrospinal fluid (CSF) levels of the beta-amyloid (Aβ) 40- and 42-amino acid species, thought to reflect the burden of vascular Aβ deposition in the brain. Little is known regarding the association of CSF Aβ reduction with specific MRI manifestations of CAA.Methods:We identified 31 patients with CAA per Boston criteria v2.0 (1 definite, 27 probable, and 3 possible), who underwent CSF sampling for measurement of Aβ42, total tau (t-tau), and phospho-tau (p-tau) as part of their evaluation with ADmark (Athena Diagnostics). We assessed the following MRI manifestations of CAA while blinded to CSF biomarkers: the presence of cortical superficial siderosis (cSS), number of lobar cerebral microbleeds (CMBs), pattern and severity of white matter hyperintensities (WMH), and number of enlarged perivascular spaces in centrum semiovale (CSO-EPVS).Results:Median age of presentation was 69 years (range 56-89). Out of 31 patients, 19 were female (61.3%), 20 (64.5%) presented with cognitive impairment, 9 (29%) with intracerebral hemorrhage, and 2 (6.5%) with transient focal neurologic events. Mean (±SD) CSF Aβ42 concentration in our cohort was 359.3±126.7 pg/ml, substantially reduced relative to that reported in healthy controls. MRI manifestations associated with reduced Aβ42 without altered tau were presence of cSS (310±136 vs. 406±101, p=0.03) and higher burden of CSO-EPVS (307±101 vs. 431±127, p=0.005). Patients presented with cognitive impairment had higher tau levels (t-tau: 551±320 vs. 317±141, p=0.03; p-tau: 75.7±39.8 vs. 49.2±22.4, p=0.05) without altered Aβ42. Similar results were obtained when patients with possible CAA were excluded.Discussion:Our results suggest that presence of cSS and higher burden of CSO-EPVS are associated with lower Aβ42 concentration in CSF, potentially reflecting higher overall burden of vascular Aβ deposition in the brain. We found that higher tau concentrations in CSF are associated with cognitive impairment, presumably reflecting concomitant Alzheimer’s disease pathology. These results help inform interpretation of this clinically accessible test in practice and suggest potential mechanisms for specific CAA-related pathologies.

Stroke, Volume 55, Issue Suppl_1, Page AWMP16-AWMP16, February 1, 2024. Background:Individual magnetic resonance imaging (MRI) markers of cerebral small vessel disease (CSVD) are associated with impaired cognition and dementia but may not reflect the overall burden of CSVD. It is unclear whether these markers provide additional value in evaluating the risk of dementia beyond assessments based solely on clinical risk factors. Thus, we aimed to determine whether the association of additive burden of multiple CSVD markers was independent of vascular risk factors and the Framingham Stroke Risk Profile (FSRP) and to also compare results with the FSRP.Methods:We included 1,152 Framingham Heart Study (FHS) participants over the age of 55, free of stroke and dementia, from the Original and Offspring cohorts with available MRI and FSRP data. CSVD score was calculated by summing the number of CSVD features detected in the MRI: cerebral microbleeds, cerebral brain infarcts, extensive white matter hyperintensities, severe perivascular spaces, and cortical superficial siderosis. Two Cox proportional hazards regression models were used to relate the multi-marker CSVD score to incident all-cause dementia and Alzheimer’s dementia. The first model adjusted for education, cohort, and clinical risk factors while the second adjusted for education, cohort, and FSRP.Results:Mean age was 70.9 years (SD: 8.7), 527 (46%) were male, and 211 (18%) had score ≥ 2. Over a median follow-up time of 6.4 years (Q1-Q3: 4.6-11.3), participants with score ≥ 2 had elevated risk of all-cause dementia compared to those with no CSVD markers after adjustment for FSRP (HR: 2.32; 95% CI: 1.46-3.69; p

Stroke, Volume 55, Issue Suppl_1, Page ATP312-ATP312, February 1, 2024. Traumatic brain injury (TBI) afflicts 70 million people worldwide annually and is the 3rd overall risk factor for developing Alzheimer’s disease (AD), behind genetics and aging. In patients with AD, a history of TBI is associated with a 3-4 year earlier onset of cognitive impairment. TBI and AD share many pathologies, including blood brain barrier dysfunction, neuroinflammation, and protein aggregation. Yet, the underlying mechanism of this relationship is not understood, and there are no treatments that protect patients from accelerated AD after TBI. We recently reported that tau, a microtubule binding protein essential for neuronal health, is acetylated after TBI. Acetylation impairs tau binding to microtubules, leading to its mis-localization into the cell soma and pathological aggregation. Acetylated tau is also elevated early in AD, and acetylated tau was significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesize that TBI-induced tau acetylation drives the acceleration of AD. To study this phenomenon, we developed a mouse model of TBI that accelerates AD-like pathology and cognitive impairment in 5xFAD mice, and amyloid-driven AD model. Our unique model of multimodal TBI produces a complex and reproducible brain injury with neurodegeneration and neurobehavioral impairment, beginning with acute axonal degeneration and persisting chronically with blood-brain barrier degradation and nerve cell death. This model of TBI also produces the same systemic metabolic alterations that are reported in TBI patients. TBI causes learning deficits in young 5xFAD mice that are not seen in either sham-injured 5xFAD mice or in wild type littermates subjected to TBI. TBI also accelerates amyloid deposition in 5xFAD mice. We hypothesize that TBI will also worsen blood brain barrier function in 5xFAD mice. Importantly, 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Preliminary data suggests that treatment with the FDA-approved non-steroidal inflammatory drug diflunisal, which inhibits the enzyme that acetylates tau, reduces acetylated tau and rescues behavior deficits after TBI in 5xFAD mice.

Stroke, Volume 55, Issue Suppl_1, Page ATMP69-ATMP69, February 1, 2024. Introduction:Cerebral hypoperfusion even in asymptomatic CASO may cause cognitive impairment. We reportedAPOE4induces neurovascular dysfunction and cognitive impairment in a mouse model of CASO. However, it has not been clinically investigated in patients with asymptomatic CASO.Methods:A cross-sectional observational study was conducted between January 2017 and March 2022. In a primary analysis, 91 patients with asymptomatic moderate or severe CASO who underwent cognitive tests, including the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog), and15O-gas positron-emission tomography (PET) were included to examine associations of cognitive impairment and cerebral hemodynamic disruption withAPOE4. To investigate hemodynamic disruption, a sensitivity analysis in 70 additional patients who underwent only15O-gas PET was performed.Results:Among the 91 patients with asymptomatic moderate or severe CASO, 20 (22.0%) wereAPOE4carriers. In a multivariable linear regression analysis,APOE4was an independent risk factor for a worse ADAS-Cog delayed word recall score, indicating short-term memory impairment (β = 0.21, 95% confidence interval (CI) 0.026–2.30,p= 0.045). The15O-gas PET showed thatAPOE4was an independent risk factor for lower cerebral blood flow (CBF) in the anterior circulation territory (β = –0.31, 95%CI –0.091 to –0.015,p= 0.007), without changes in cerebral metabolic rate of oxygen (CMRO2) or oxygen extraction fraction. Of 161 patients in the sensitivity analysis, 31 (19.3%) carriedAPOE4, which was an independent predictor of lower CBF (β = –0.23, 95%CI –0.072 to –0.014,p= 0.004) in the anterior circulation territory.Conclusions:APOE4may confer an increased risk of memory impairment accompanied by cerebral hemodynamic disruption in asymptomatic CASO. The present study indicated that identifyingAPOE4in such patients may be useful in early detection of disease severity.

Stroke, Volume 55, Issue Suppl_1, Page AWP308-AWP308, February 1, 2024. Introduction:Respiratory disorders, including sleep apnea, are an independent risk factor for the development of cognitive dysfunction and dementia. Disordered breathing occurs frequently in patients with AD (Alzheimer’s Disease). Disruption of the brainstem breathing centers, including the Retro-trapezoid nucleus (RTN), leads to breathing disorders. Our previous work showed that upregulation of Transforming Growth Factor Beta Receptor 2 (TGFBR2) signaling in the RTN leads to respiratory dysfunction in mice. The present study investigated if inhibiting TGFBR2 selectively in the RTN region could improve breathing and cognitive function in AD mice.Methods:We used 20 WT and 20 TG2576 mice (15 months old). Mice were randomly assigned into two sub-groups; treatment with a shTGFBR2 vector (knockdown) or vector control with scrambled shRNA. After baseline behavior and breathing testing, lentiviral stereotaxic injections of vehicle and shTGFBR2 were done directly into the RTN. After 6 weeks, behavior and breathing testing was performed, and then brain tissues were collected for histological analysis. All the data are presented as Mean±SEM.Results:Tg2576 mice had significantly higher number of apnea (7.91±0.95) than WT mice (4.10±0.85) with ap-value of 0.0079. When injected with shTGFBR2 into the RTN, Tg2576 had improved recognition of a novel object (69.24%±5.75) as compared to the Tg2576 vehicle-treated group (51.02%±4.88) in the NORT (p=0.0213). They also showed a significant improvement in the latency to escape (64.94±15.56) compared to the Tg2576 vehicle-treated group (136.4±20.90) in the Barnes maze (p=0.0109). The number of apneas was also significantly reduced in TG2675 mice treated with shTGFBR2 in the RTN (3.33±0.69), when compared to the Tg2576 vehicle-treated group (8.22±1.30) with ap-value of 0.0029.Conclusions:Our study revealed that the knockdown of TGFBR2 in the RTN, a brainstem nucleus involved in respiratory control, improved both the cognitive and breathing phenotypes in AD-model mice. Our work suggests that improving respiratory control and reducing apnea in AD may be a potential treatment for the disease. This is especially relevant as new treatments for central apnea, such as phrenic nerve stimulation, are available.

Stroke, Volume 55, Issue Suppl_1, Page ATP238-ATP238, February 1, 2024. Introduction:Stroke and transient ischemic attack (TIA) increase risk for cognitive impairment and dementia. Without a lasting infarction, the cause of cognitive decline after TIA remains unknown. We hypothesize that these cerebrovascular accidents (CVAs) have long-term negative effects on the blood brain barrier (BBB) and promote endothelial inflammation, both of which are associated with neurodegeneration. We sought to investigate the effects of CVAs on BBB integrity and endothelial inflammation by evaluating PDGFRβ and VCAM-1 serum levels, respectively.Methods:A subset of 88 subjects in the Arizona Study of Aging and Neurodegenerative Disorders with postmortem serum samples were available for analysis. Sandwich ELISA was performed to detect PDGFRβ and VCAM-1. Statistical analyses were performed using Spearman’s rank correlation and Mann Whitney U test.Results:Our subjects were split based on CVA status and matched according to vascular risk factors. Both subjects with stroke and subjects with TIA had increased serum PDGFRβ compared to those without history of CVA (6608.4 pg/mL and 5337.0 pg/mL, P=0.04, and 7849.5 pg/mL vs. 5337.0 pg/mL, P

Stroke, Volume 55, Issue Suppl_1, Page ATMP115-ATMP115, February 1, 2024. Cerebral amyloid angiopathy (CAA) is a disease of small and medium-sized vessels, characterized by amyloid deposition in the brain vasculature. The incidence of CAA increases with age and pathophysiological features (i.e., amyloid) overlap with that of Alzheimer’s Disease (AD). Cerebral hypoperfusion (CH) impairs the integrity of the blood brain barrier and contributes to cerebral atrophy and white matter loss. However, the link between hypoperfusion and vascular amyloid deposition remains understudied. We induced global CH with bilateral carotid artery stenosis (BCAS) in CAA mice of both sexes. We hypothesized that chronic CH accelerates cognitive decline in CAA, increases white matter damage, and induces gliotic changes in the brain. Using a mouse model of CAA (Tg-SwDI), male and female mice (12wks-old) were randomized to either BCAS (n=15) or sham (n=11) surgery. Cognitive (Y-maze (YM), NORT, Water Maze (WM)) and motor function (Open Field (OF)) testing was performed by a blinded investigator prior to surgery (baseline) and at regular intervals until tissue harvest 6 months post-BCAS. Brains were harvested for immunohistochemical (IHC) analysis (Kluver-Barrera (KB), Iba-1, GFAP, Myelin Basic Protein (MBP)) and flow cytometry. Sex-specific changes in spatial memory (YM) and learning (NORT/WM) were present in CAA BCAS mice, with females having an earlier onset of deficits than males. Female BCAS mice displayed deficits in cognition (NORT) at 3 (p=.003), 4 (YM, p=.0007), and 5-months (p=.01) after BCAS. Male BCAS mice demonstrated cognitive deficits 5 months post-BCAS (NORT, p=.001). Both female and male BCAS mice had poorer cognition (WM, p=.001) 6 months post-BCAS. IHC demonstrated increased demyelination (MBP, p=.004) and atrophy (KB) in the anterior corpus collosum (p=.04) and significant cortical gliosis (p=.02). The hippocampus contained higher numbers of NOX2-expressing (p= .051) and lipid-rich microglia in BCAS (p=.042) versus sham mice. Neuronal loss and increases in endothelial-cell amyloid levels were also found in BCAS CAA mice, using flow cytometry. Global CH accelerates cognitive deficits in a CAA model, an effect that is accelerated in female mice and led to gliosis, white matter damage, and lipid-accumulating microglia.

Studio ISS, IRCCS Milano, ‘nel 2020 23,7 milioni dai 16,8 del 2010’

Studio ISS, IRCCS Milano, 23,7 milioni nel 2020 da 16,8 del 2010

Sottoposta a un intervento chirurgico urgente all’intestino

Annals of Internal Medicine, Ahead of Print.

Annals of Internal Medicine, Ahead of Print.